Prostaglandin I2 (PGI2) is produced from arachidonic acid via prostaglandin H2 (PGH2) in the living body and has various potent pharmacological effects such as inhibition of platelet aggregation, vasodilation, inhibition of lipid deposition, and inhibition of leucocyte activation. It is therefore considered that PGI2 is effective for treatment of peripheral vascular diseases (for example, arteriosclerosis obliterans, intermittent claudication, peripheral arterial embolism, vibration disease, and Raynaud's disease), systemic lupus erythematosus, reocclusion or restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis, diabetic neuropathy, diabetic nephropathy, hypertension, ischemic diseases (for example, cerebral infarction and myocardial infarction), transient ischemic attack and glomerulonephritis, or acceleration of angiogenesis in peripheral blood vessel reconstruction technique or angiogenesis therapy.
However, PGI2 is not suited for use as a medicine because it is chemically unstable and has very short biological half-life, and also has such a problem that side effect is likely to arise because it is difficult to separate the desired effect from the other effect. For the purpose of persistence of drug efficacy, relief of side effect and improvement of compliance, long acting preparations of prostaglandins have been researched and developed. However, satisfactory results have never been achieved.
Under these circumstances, it is expected that a PGI2 receptor agonist, which is non-prostanoid and has excellent affinity to PGI2 receptor and chemical stability, exerts excellent therapeutic effect a medicine as compared with conventional PGI2 preparations, and thus it has intensively been researched and developed.
For example, it has been known that imidazole derivatives (Br. J. Pharmcol., 102, 251 (1991)), oxazole derivatives (J. Med. Chem., 35, 3498 (1992), J. Med. Chem., 36, 3884 (1993)), pyrazole derivatives (Folia Phermacol. Jp., 106, 181 (1995), Bioorg. Med. Chem. Lett., 5, 1071 (1995), Bioorg. Med. Chem. Lett., 5, 1083 (1995)), pyrazinone derivatives (Bioorg. Med. Chem. Lett., 10, 2787 (2000)) and oxime derivatives (Folia Phermacol. Jp., 106, 181 (1995), Bioorg. Med. Chem. Lett., 5, 1071 (1995), Bioorg. Med. Chem. Lett., 5, 1083 (1995)) have PGI2 receptor agonistic activity.
Also it is known that 2,3-diphenylpyrazine derivatives (Japanese Unexamined Patent Publication No. Hei-7-33752) have a herbicidal effect, 2,3-diphenylpyridine derivatives and 5,6-diphenylpyrimidine derivatives (WO92/01675) have a leukotriene B4 antagonism and 2,3-diphenylpyridine derivatives (WO96/18616) have a nitric oxide synthesis inhibitory effect. However, it is not known that these compounds have a PGI2 receptor agonistic activity.